This application addressed Broad Challenge Area: (03) Biomarker Discovery and Validation and specific challenge topic: 03-AT-101* Psychoneuroimmunology biomarkers of stress. Identification of biomarkers to assess the impact of stress, both social and biological, on immune function. The rate of cell senescence in lymphocytes (particularly in CD8 cells), as indicated by decreases in telomere length, may be an important new marker of immunocompetence and, in turn, host resistance to infectious agents. Loss of telomere length may be especially important in understanding the role of psychological stress in infectious illness. Stress is associated with greater susceptibility to upper respiratory viral illnesses. In addition, increases in psychological stress are associated with shorter telomere length in lymphocytes. This evidence suggests that stress may influence disease susceptibility via its effects on lymphocyte cell senescence. Moreover, psychological stress has also been associated with greater oxidative stress and less telomerase activity. Both of these contribute to shortening of telomeres, suggesting that psychological stress may shorten telomeres via its effects on these telomere regulators. We have a unique opportunity to address these hypotheses in healthy adult human subjects by adding assessments of oxidative stress, telomerase activity and telomere length at baseline to an ongoing viral- challenge study. Baseline measures in the parent study include a range of stress measures: psychological and social measures of stress by questionnaire, assessments of basal diurnal cortisol rhythms over three days and of autonomic and cortisol response to an experimental stressor in the laboratory. After completing all baseline measures, subjects are exposed to a safety tested rhinovirus and monitored in quarantine for the development of infection and illness. Local (nasal secretory) release of pro- and anti- inflammatory cytokines are also assessed after viral exposure. Approximately 40% of the subjects develop a clinical illness in response to the viral challenge. In this extension of that study, we propose to evaluate whether telomere length predicts susceptibility to infection and disease expression and whether it constitutes a mediating pathway through which stress influences resistance to infectious disease. We can also determine whether or not telomere length mediates the known effects of psychological stress on the locally produced pro- and anti-inflammatory cytokines that play a role in illness expression. Finally, we can test whether or not telomerase activity and oxidative stress constitute pathways through which psychological, social and biological markers of stress might influence telomere length. This work has implications for understanding the role of stress in the aging process and particularly important implications for reducing disease in the elderly and those experiencing long-term stress (e.g. the chronically unemployed, caregivers, and those suffering from poverty). PUBLIC HEALTH RELEVANCE: A major focus of the project is to determine whether immune cell senescence (as assessed by telomere length) plays an important role in our ability to fight off infection. Because life stress has been found to be associated with greater senescence, we are also testing whether stress-associated increases in senescence can account for why life stress increases our risk for infectious diseases. An in-depth understanding of the role how stress influences our health can help lead to effective interventions to protect people at risk.